Introduction to Strategies for Organic Synthesis

The stepping-stone text for students with a preliminary knowledge of organic chemistry looking to move into organic synthesis research and graduate-level coursework Organic synthesis is an advanced but important field of organic chemistry, however resources for advanced undergraduates and graduate students moving from introductory organic chemistry courses to organic synthesis research are scarce. Introduction to Strategies for Organic Synthesis is designed to fill this void, teaching practical skills for making logical retrosynthetic disconnections, while reviewing basic organic transformations, reactions, and reactivities. Divided into seven parts that include sections on Retrosynthesis and Protective Groups; Overview of Organic Transformations; Synthesis of Monofunctional Target Molecules; Synthesis of Target Molecules with Two Functional Groups; Synthesis of Aromatic Target Molecules; Synthesis of Compounds Containing Rings; and Predicting and Controlling Stereochemistry, the book covers everything students need to successfully perform retrosynthetic analyses of target molecule synthesis. Starting with a review of functional group transformations, reagents, and reaction mechanisms, the book demonstrates how to plan a synthesis, explaining functional group analysis and strategic disconnections. Incorporating a review of the organic reactions covered, it also demonstrates each reaction from a synthetic chemist's point of view, to provide students with a clearer understanding of how retrosynthetic disconnections are made. Including detailed solutions to over 300 problems, worked-through examples and end-of-chapter comprehension problems, Introduction to Strategies for Organic Synthesis serves as a stepping stone for students with an introductory knowledge of organic chemistry looking to progress to more advanced synthetic concepts and methodologies.

Table of Contents:
Preface PART I Synthetic Toolbox 1: Retrosynthesis and Protective Groups 1 CHAPTER 1.1 Retrosynthetic Analysis 3 Retrosynthesis by Functional Group Interconversion (FGI) 4 Retrosynthesis by Making a Disconnection 6 CHAPTER 1.2 Protective Groups 11 Protection of Ketones and Aldehydes 12 Protection of Alcohols 12 Protection of Carboxylic Acids 16 Protection of Amines 17 Part I Problems Protective Groups 19 PART II Synthetic Toolbox 2: Overview of Organic Transformations 21 CHAPTER 2.1 Nucleophiles and Electrophiles 23 Common Nucleophiles 23 Common Electrophiles 26 CHAPTER 2.2 Oxidation and Reduction Reactions 27 Overview of Oxidations and Reductions 27 Common Oxidation Reactions and Oxidizing Agents 29 Common Reduction Reactions and Reducing Agents 35 Part II Problems Nucleophiles, Electrophiles, and Redox 41 PART III Synthesis of Monofunctional Target Molecules (1-FG TMs) 45 CHAPTER 3.1 Synthesis of Alcohols (ROH) 47 Synthesis of Alcohols by Functional Group Interconversion (FGI) 48 Synthesis of Alcohols by the Grignard Reaction 50 Synthesis of Propargylic Alcohols (RC=CCH2OH) 56 Synthesis of Phenol Derivatives (ArOH) 57 Example: Alcohol TM 58 CHAPTER 3.2 Synthesis of Alkyl (RX) and Aryl Halides (ArX) 61 Synthesis of Alkyl Halides via Free-Radical Halogenation 61 Synthesis of Alkyl Halides via FGI 62 Retrosynthesis of Alkyl Halides 63 Synthesis of Aryl Halides (ArX) 63 Example: Alkyl Halide TM 64 CHAPTER 3.3 Synthesis of Ethers (ROR') 67 Williamson Ether Synthesis (RX + R'O- ? ROR') 67 Alternate Ether Preparations 68 Synthesis of Epoxides 69 Retrosynthesis of Ethers 70 Example: Ether TM 71 CHAPTER 3.4 Synthesis of Thiols (RSH) and Thioethers (RSR') 73 Example: Thioether TM 75 CHAPTER 3.5 Synthesis of Amines (RNH2) and Anilines (ArNH2) 77 Synthetic Equivalents of NH3 (RX ? RNH2) 78 Synthesis of Amines via Reduction Reactions 80 Retrosynthesis of Amines 82 Synthesis of Aniline Derivatives (ArNH2) 82 Example: Amine TM 83 CHAPTER 3.6 Synthesis of Alkenes (R2C=CR2) 85 Synthesis of Alkenes via FGI 85 Synthesis of Alkenes via the Wittig Reaction 88 Example: Alkene TM 90 CHAPTER 3.7 Synthesis of Alkynes (RC=CR') 93 Synthesis of Alkynes via FGI 93 Synthesis of Alkynes from Other Alkynes (RC=CH ? RC=CR') 94 Example 1: Alkyne TM 95 Example 2: Alkyne TM 95 CHAPTER 3.8 Synthesis of Alkanes (RH) 97 Synthesis of Alkanes via FGI 97 Synthesis of Alkanes via C-C Bond Formation 99 Retrosynthesis of Alkanes 101 Example: Alkane TM 102 CHAPTER 3.9 Synthesis of Aldehydes and Ketones (RCHO, R2C=O) 105 Synthesis of Aldehydes/Ketones via FGI 105 Synthesis of Aldehydes/Ketones via Acyl Substitutions 107 Synthesis of Ketones via a-Alkylation 109 Example: Ketone TM 113 CHAPTER 3.10 Synthesis of Carboxylic Acids (RCO2H) 115 Synthesis of Carboxylic Acids via FGI 115 Synthesis of Carboxylic Acids via Grignard (RMgBr + CO2 ? RCO2H) 116 Carboxylic Acids via a-Alkylation: Malonic Ester Synthesis 117 Example: Carboxylic Acid TM 119 CHAPTER 3.11 Synthesis of Carboxylic Acid Derivatives 121 Relative Reactivities of Carboxylic Acid Derivatives (RCOLG) 121 Synthesis of Acid Chlorides (RCOCl) 123 Synthesis of Anhydrides (RCO2COR) 124 Synthesis of Esters (RCO2R) 124 Synthesis of Amides (RCONH2) 128 Synthesis of Nitriles (RC=N) 131 Example: Carboxylic Acid Derivative 132 Part III Problems Monofunctional Target Molecules (1-FG TMs) 135 PART IV Synthesis of Target Molecules with Two Functional Groups (2-FG TMs) 139 CHAPTER 4.1 Synthesis of ss-Hydroxy Carbonyls and a,ss-Unsaturated Carbonyls 141 The Aldol Reaction 141 Synthesis of a,ss-Unsaturated Esters Using the Wittig Reaction 149 Example: a,ss-Unsaturated Carbonyl 150 CHAPTER 4.2 More Enolate Reactions: Synthesis of 1,3-Dicarbonyls, 1,5-Dicarbonyls, and Cyclohexenones 153 The Claisen Condensation 153 The Michael Reaction 157 Summary of Enolate Syntheses 161 Robinson Annulation 162 CHAPTER 4.3 "Illogical" Disconnections: Umpolung (Polarity Reversal) 165 Synthesis of TMs with a 1,2-Dioxygenated Pattern 165 Synthesis of TMs with a 1,4-Dioxygenated Pattern 171 Synthesis of TMs with a 1,6-Dicarbonyl Pattern 175 Part IV Problems Target Molecules with Two Functional Groups (2-FG TMs) 177 PART V Synthesis of Aromatic Target Molecules 181 CHAPTER 5.1 Electrophilic Aromatic Substitution (ArH + E+ ? ArE) 183 Mechanism of the Electrophilic Aromatic Substitution 183 Electrophiles for the Electrophilic Aromatic Substitution 183 Electrophilic Aromatic Substitution on Substituted Benzenes 185 Retrosynthesis of Aromatic TMs (Electrophilic Aromatic Substitution) 191 Example: Aromatic TM 1 193 CHAPTER 5.2 Synthesis of Aromatic TMs via Diazonium Salts (ArN2+ + Nu ? ArNu) 195 Preparation of Diazonium Salts (ArNH2 ? ArN2+) 195 Use of Diazonium Salts (ArN2+ + Nu ? ArNu) 195 Retrosynthesis of Aromatic TMs (via Diazonium Salts) 196 Example: Aromatic TM 2 197 CHAPTER 5.3 Nucleophilic Aromatic Substitution (ArX + Nu: ? ArNu) 199 Mechanism of Nucleophilic Aromatic Substitution (SNAr) 199 Retrosynthesis of Aromatic TMs (SNAr) 200 Example: Aromatic TM 3 201 Part V Problems Aromatic TMs 203 PART VI Synthesis of Compounds Containing Rings 207 CHAPTER 6.1 Synthesis of Cyclopropanes 209 Retrosynthesis of Cyclopropane TMs 210 CHAPTER 6.2 Synthesis of Cyclobutanes 213 Retrosynthesis of Cyclobutane TMs 213 CHAPTER 6.3 Synthesis of Five-Membered Rings (Radical Cyclization Reactions) 215 Baldwin's Rules 216 Retrosynthesis of Methylcyclopentane TMs 216 Example: Methylcyclopentane TM 217 CHAPTER 6.4 Synthesis of Six-Membered Rings (Diels Alder Reaction) 219 The Dienophile (E+) 220 The Diene (Nu:) 221 Regiochemistry of the Diels-Alder 223 Retrosynthesis of Cyclohexenes (Diels-Alder) 225 Retrosynthesis of 1,4-Cyclohexadienes 226 Part VI Problems Cyclic TMs 229 PART VII Predicting and Controlling Stereochemistry 233 CHAPTER 7.1 Reactions That Form Racemates 235 Formation of New Chiral Carbons 235 Loss of a Group from a Chiral Carbon: Racemization 238 CHAPTER 7.2 SN2 Mechanism: Backside Attack 241 CHAPTER 7.3 Elimination Mechanisms 243 E2 Elimination (Anti) 243 Cope Elimination (Syn) 244 CHAPTER 7.4 Additions to Alkenes and Alkynes 245 Syn Additions 245 Anti Additions 246 CHAPTER 7.5 Additions to Carbonyls 249 Diastereoselectivity in Acyclic Systems: Cram's Rule, Felkin-Ahn Model 249 Chelation Control by Neighboring Groups 251 Addition to Cyclohexanones 252 CHAPTER 7.6 Additions to Enolates: Aldol Stereochemistry 253 Formation of (E) and (Z) Enolates 253 Aldol Reaction with (E) and (Z) Enolates 254 Examples: Predicting Aldol Stereochemistry 255 CHAPTER 7.7 Enantioselectivity and Asymmetric Syntheses 257 Prochiral Environments 257 Enantioselective Techniques 259 Part VII Problems Stereochemistry 263 Solutions to Problems 267 Solutions to Part I: Protective Groups 267 Solutions to Part II: Nucleophiles, Electrophiles, and Redox 270 Solutions to Part III: Monofunctional Target Molecules (1-FG TMs) 274 Solutions to Part IV: Difunctional Target Molecules (2-FG TMs) 286 Solutions to Part V: Aromatic TMs 303 Solutions to Part VI: Cyclic TMs 310 Solutions to Part VII: Stereochemistry 320 Index 331